High Regression Rate Research Articles

A multi-centre randomised controlled trial comparing megestrol acetate to levonorgestrel-intrauterine system in fertility sparing treatment of atypical endometrial hyperplasia.

The objective of the trial was to compare the regression rate of atypical endometrial hyperplasia (AEH) in patients treated with megestrol acetate (MA) vs. levonorgestrel-intrauterine device (LNG-IUS). We also aimed to assess the fertility and pregnancy outcomes in these patients. The study was a phase II multi-centre randomised controlled trial on the use of MA compared to LNG-IUS in the treatment of AEH conducted from January 2020 to January 2024 in Singapore. Women who were diagnosed with AEH and between 21 and 40years old were included. The patients were randomised to receive either MA (160mg orally daily) or LNG-IUS. The primary outcomes assessed were the regression rates at 3months, 6months and 9months of treatment. The secondary outcomes assessed were the side effects, patient acceptability and fertility outcomes. Thirty-six patients completed the trial. The overall regression rate was 88.9% by 9months. There was no statistically significant difference in the 9-month complete regression rate between MA vs. LNG-IUS. There was also no significant difference in side effects and weight change between both arms. Nineteen patients were actively pursuing fertility after complete regression. There were 8 pregnancies achieved, with resultant 4 live births and 4 miscarriages. Our study confirms a high regression rate of AH with medical treatment. LNG-IUS is a non-inferior treatment compared to megestrol acetate. Successful pregnancy outcomes can be achieved after regression of AEH. Long-term studies of sufficient sample-size are needed to assess for fertility and pregnancy outcomes, risk of recurrence and long-term risk of malignancy. The study was registered with the Health Science Authority (HSA) (License No.: CTA1900087) on September 5, 2019: https://eservice.hsa.gov.sg/prism/ct_r/enquiry.do?action=loadSpecificDetail . The trial was registered retrospectively on ClinicalTrials.gov (ID: NCT05492487) on April 7, 2022: https://clinicaltrials.gov/study/NCT05492487 .

The efficacy of levonorgestrel intrauterine device, medroxyprogesterone acetate, and norethisterone acetate in the treatment of endometrial hyperplasia without atypia

Objectives: Pregestational treatments, which trigger apoptosis and suppress endometrium, are the gold standard therapy for endometrial hyperplasia without atypia. The levonorgestrel-intrauterine device is the first choice in current guidelines due to its low dose. Still, oral progestins have no clear evidence due to their lower regression rates and side effects. Here, we aimed to compare the regression rates, hysterectomy requirement, and the occurrence of side effects in the sixth month between the levonorgestrel-intrauterine device, norethisterone acetate, and medroxyprogesterone acetate treatment. Methods: A total of 60 patients were included. The study group was divided into three groups: levonorgestrel-intrauterine device group (n=20), norethisterone acetate group (n=20), and medroxyprogesterone acetate group (n=20). Demographic findings, body mass index, gravida, parity, comorbid diseases, regression, hysterectomy requirement, patient desire to continue treatment, and side effects such as amenorrhea, headache, weight gain, intermenstrual spotting, nausea, and breast tenderness were compared between three groups. Results: There was no statistically significant difference between the three groups regarding headache, weight gain, intermenstrual spotting, and breast tenderness. Regression rates were significantly higher in the levonorgestrel intrauterine device group compared to medroxyprogesterone acetate (p=0.044) and norethisterone acetate group (p=0.020). Similarly, hysterectomy rates were significantly lower in the levonorgestrel intrauterine device group compared to medroxyprogesterone acetate (p=0.031) and norethisterone acetate group (p=0.028). Amenorrhea was significantly more common in the levonorgestrel intrauterine device group than in other groups (p=0.020 for both), whereas nausea was rarer in the levonorgestrel intrauterine device group (p=0.047 for both). According to the patient’s satisfaction, the levonorgestrel intrauterine device was the most satisfactory treatment compared to medroxyprogesterone acetate and norethisterone acetate (p=0.028 and p=0.031). No significant difference was found between the medroxyprogesterone acetate and norethisterone acetate groups in terms of regression rates, hysterectomy requirements, amenorrhea, nausea, and patient satisfaction. Conclusion: Considering low hysterectomy requirement, high regression rates, and patient satisfaction, the levonorgestrel intrauterine device should be the first choice for endometrial hyperplasia without atypia as compared to oral progestins. Thus, patients must be informed about side effects and offered levonorgestrel intrauterine devices before oral progestins for endometrial hyperplasia without atypia.

ALK5/VEGFR2 dual inhibitor TU2218 alone or in combination with immune checkpoint inhibitors enhances immune-mediated antitumor effects

Transforming growth factor β (TGFβ) is present in blood of patients who do not respond to anti-programmed cell death (ligand) 1 [PD-(L)1] treatment, and through synergy with vascular endothelial growth factor (VEGF), it helps to create an environment that promotes tumor immune evasion and immune tolerance. Therefore, simultaneous inhibition of TGFβ/VEGF is more effective than targeting TGFβ alone. In this study, the dual inhibitory mechanism of TU2218 was identified through in vitro analysis mimicking the tumor microenvironment, and its antitumor effects were analyzed using mouse syngeneic tumor models. TU2218 directly restored the activity of damaged cytotoxic T lymphocytes (CTLs) and natural killer cells inhibited by TGFβ and suppressed the activity and viability of regulatory T cells. The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFβ signaling. The combination of TU2218 and anti-PD1 therapy had a significantly greater antitumor effect than either drug alone in the poorly immunogenic B16F10 syngeneic tumor model. The mechanism of tumor reduction was confirmed by flow cytometry, which showed upregulated VCAM-1 expression in vascular cells and increased influx of CD8 + CTLs into the tumor. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.

Gastric intestinal metaplasia regression in United States population: A retrospective longitudinal study.

Gastric cancer is a health concern and contributes to cancer-related deaths. Gastric intestinal metaplasia (GIM) is a premalignant lesion of gastric cancer. Currently, factors associated with GIM regression are under-investigated. This study aims to assess the rate of GIM regression and identify factors associated with it. This study was conducted at Medstar Washington Hospital Center. We included patients who had GIM between January 2015 and December 2020. Population was divided into GIM persistence or regression. Data included demographics, esophagogastroduodenoscopy findings, Helicobacter pylori status, and laboratory results. Statistical analyses included Kaplan-Meier and Cox proportional models to explore predictors of GIM regression. Among 2375 patients, 9.1% had GIM. Notably, 85 patients had GIM regression and 132 patients had persistent GIM. African Americans constituted (75%) of the regression group and (76%) of the persistence group. Peptic ulcer disease (PUD) was noted in 12.9% of the regression group at baseline, and 5.9% at follow-up; the persistence group showed 11.4% at baseline and 5.3% at follow-up (P = 0.89). Regression analysis revealed that the presence of PUD was associated with a higher rate of regression (hazard ratio [HR] 2.46, P = 0.013). Smoking status showed lower rates of regression (HR 0.54 and 0.62, P = 0.038 and 0.169). On gastric mapping, African Americans, Hispanics, and individuals of other races/ethnicities displayed lower rates of GIM regression (HR 0.68, 0.78 and 0.69). PUD was associated with a higher rate of GIM regression, while smoking showed lower regression rates. Results provide insights into factors influencing GIM regression in African American population and may inform future surveillance and treatment strategies.

Comparison of Intravitreal Ranibizumab and Laser Photocoagulation in the Treatment of Type I Retinopathy of Prematurity in Malaysia: A One-Year Follow-Up Study.

This study aimed to evaluate the treatment efficacy, anatomical outcomes, and refractive outcomes of laser photocoagulation (LPC) and intravitreal ranibizumab (IVR) in the treatment of type I retinopathy of prematurity (ROP) at one-year follow-up. This is a retrospective study on the treatment of type I ROP and aggressive ROP (A-ROP) using LPC or IVR in three Malaysian hospitals providing pediatric ophthalmology services from January 2019 to December 2021. Information on gestational age, birth weight, ROP zone and stage, and underlying comorbidities was collected. Parameters for evaluating treatment efficacy include the time taken to achieve complete regression, the regression rate, and the reactivation rate. The anatomical and refractive outcomes were evaluated at one year of adjusted age. This study included 92 eyes from 46 infants. Of these, 42 eyes received LPC as the initial treatment, while 50 eyes underwent IVR. A higher percentage of infants with cardiovascular disease were treated with IVR (66.7%) compared to LPC (40%) (p<0.05). However, there were no significant differences in gestational age, birth weight, respiratory distress syndrome, sepsis, or intraventricular hemorrhage between the two treatment groups (p>0.05). Infants treated with LPC had a higher regression rate than those treated with IVR, but they were also significantly more myopic and had worse best-corrected visual acuity (BCVA). Conversely, infants treated with IVR experienced a significantly higher reactivation rate compared to those treated with LPC. Logistic regression analysis showed no significant associations between gestational age, birth weight, plus disease, zone 1 ROP, and the choice of initial treatment with the reactivation of ROP. Both LPC and IVR effectively treat type I ROP in infants, with IVR yielding superior anatomical and refractive outcomes and LPC offering a lower reactivation rate. Understanding individual patient characteristics is crucial for treatment selection.

Improving the effectiveness of cervical cancer screening: Managing positive high-risk human papillomavirus results.

Good compliance of the management of abnormal results is important for effective cervical screening. This study investigated the rate of surveillance and follow-up outcomes for human papillomavirus (HPV)-positive women in cervical screening. Women on surveillance by repeat HPV testing were identified in a prospectively managed database. Data retrieved included women's age, country residence status, history of colposcopy, HPV-DNA status on the first and repeat tests, dates of follow-up during the 5 years since the initial screening, and histological diagnosis of cervical lesions. The main outcome measures were compliance rate for repeat HPV testing, regression and persistence rates of HPV subtypes, and detection rate of high-grade lesions (CIN2+). This analysis included 680 residents in the community, mean age 44.8 (95% confidence interval 20.1-69.5) years. The compliance rate of repeat testing was 28.2% at 12 months and, cumulatively, 42.8% for the entire 5-year follow-up period. The rates were unaffected by age (P=0.5829) nor prior colposcopy (P=0.1607). There were 5 (1.7%) cases of CIN2+ detected. Of 391 women on longitudi-nal follow-up, 194 (60.8%) cleared their HPV infection. Some women with multiple HPV infection cleared 1 but not the other subtype(s). Thus, the regression rate was 90.3% for HPV-16, 87.0% for HPV-18 and 65.2% for HPV-12-others (P=0.001). The annualised HPV regression rates were similar for HPV subtypes and for each follow-up year. Surveillance of HPV positivity is clinically important for detecting high-grade lesions. Despite a high regression rate of HPV, surveillance hesitancy is a serious weakness in routine cervical screening.

Effect of prostaglandin treatment on the estrus behaviour, follicular and luteal morphometry and serum hormone profile in sub-estrus buffaloes during non-breeding season.

Sub-estrus buffaloes do not exhibit estrus signs despite being cyclic contributing to extended service periods and inter-calving intervals causing significant economic loss. The present study described the effect of synthetic prostaglandin (PGF2α) on estrus behaviour, follicular and luteal morphometry, and serum estradiol (E2) and progesterone (P4) profile in sub-estrus buffaloes during the non-breeding season. The incidence of sub-estrus was 38.4% during the non-breeding season. The sub-estrus buffaloes (n = 33) were divided into two groups, viz., Control (n = 16) and PGF2α treatment (Inj. Cloprostenol 500 μg, i.m., n = 17). Estrus induction response was significantly greater in the treatment (100 vs. 18.75%, p < .001), and a relatively greater proportion of animals conceived in the treatment group (29.41 vs. 6.25%, p = .08). The time elapsed to induction of estrus and insemination following treatment was significantly lower in the treatment group than control. A significant increment in the follicle diameter (9.72 ± 0.45 vs. 13.00 ± 0.45 mm, P < .0001) and serum estradiol (E2) concentration (66.01 ± 11.92 vs. 104.9 ± 13.21 pg/mL, p = .003) observed at the post-treatment period in the PGF2α treatment group. At the same time, CL diameter was reduced significantly at a higher regression rate in the PGF2α treated buffaloes than those of control. Of the responded buffaloes, only 30% showed high-intensity estrus attributed to the expulsion of cervico-vaginal mucus (CVM), uterine tonicity, micturition, and mounting response by a teaser bull. From this study, it can be concluded that the administration of PGF2α could induce estrus in the sub-estrus buffaloes during the non-breeding season. Behavioural changes, along with sonographic observation of POF, regressing CL, and serum E2 and P4 concentration would be useful to determine the right time of insemination in sub-estrus buffaloes during non-breeding season.

Chinese guidelines on the management of endometrial hyperplasia

• Endometrial hyperplasia can be classified as either hyperplasia without atypia or atypical hyperplasia.• Abnormal uterine bleeding is the most common symptom of endometrial hyperplasia. Transvaginal ultrasound is recommended for initial imaging to evaluate endometrial hyperplasia (evidence level 2+), while transrectal ultrasound is recommended for virgo patients (evidence level 3).• Endometrial biopsy should be used to confirm diagnosis in patients where endometrial lesions are suspected. Effective histological approaches to make definite diagnoses include diagnostic curettage (evidence level 2++), hysteroscopic-guided biopsy (evidence level 2+) and endometrial aspiration biopsy (evidence level 2-).• Progesterone is the preferred medication for the treatment of endometrial hyperplasia without atypia. Compared to oral progestins, placement of a levonorgestrel-releasing intrauterine system (LNG-IUS) has been associated with higher regression rates, lower recurrence rates and fewer adverse events which can be the initial treatment method. (Meta evidence level 1-, RCT evidence level 2+). Ultrasound and endometrial biopsies should be performed every 6 months during treatment to evaluate its effect and treatment should continue until no pathological changes are observed in two consecutive endometrial biopsies. Hysterectomy is not the preferred choice of treatment for patients with endometrial hyperplasia without atypia.• Minimally invasive hysterectomy is indicated for patients with endometrial atypical hyperplasia (evidence level 1+), bilateral fallopian tubes should also be removed (evidence level 2+). In cases where surgery cannot be tolerated, fertility is desired or the patient is younger than 45 years old, medical therapy is recommended (evidence level 3). LNG-IUS is the preferred medical therapy method (evidence level 2+). Endometrial pathologic evaluation should be performed every 3 months during conservative treatments, with adjustments made to dosages or approaches based on observed response to medication. Treatment should continue until no pathological changes are detected in two consecutive endometrial biopsies (evidence level 2++). There is no indication of sentinel lymph nodes biopsy and/or lymphadenectomy for hyperplasia with or without atypia.• Total hysterectomy is recommended to treat patients with recurrent endometrial atypical hyperplasia (evidence level 3); however, medical conservative therapy may be considered for patients hoping to become pregnant in the future.• Patients with fully regressed disease who would like to become pregnant should be advised to seek assistance through assisted reproductive technologies (evidence level 3).• Long-term follow-up is suggested for patients after endometrial hyperplasia treatment (evidence level 2+). Patient education is imperative for improving medication adherence, increasing regression rates and lowering recurrence rates (evidence level 3).

Long-term efficacy and safety of brolucizumab in neovascular age-related macular degeneration: A multicentre retrospective real-world study.

To investigate the long-term efficacy and safety of intravitreal brolucizumab (BRZ) injections in patients with typical neovascular age-related macular degeneration (typical nAMD) and polypoidal choroidal vasculopathy (PCV). This multicentre retrospective study included 401 eyes of 398 patients with nAMD who received BRZ injection(s), with a follow-up duration of ≥12 months. Changes in best-corrected visual acuity (BCVA), retinal fluid evaluation and central subfield thickness (CST) on optical coherence tomography were assessed. The efficacy of BRZ was compared between typical nAMD and PCV groups. Analyses were conducted with 280 eyes of 278 patients with typical nAMD and 121 eyes of 120 patients with PCV (mean age, 71.1 ± 8.6 years). 29 eyes (7.2%) were treatment naïve. The mean follow-up period was 15.3 ± 2.8 months; the mean number of BRZ injections within 1 year was 4.5 ± 1.7. BCVA was maintained during the follow-up period, and CST significantly improved from the first injection month and was maintained for 12 months in both the typical nAMD and PCV groups. The dry macula proportion increased from 2.7% at baseline to 56.1% at 1 month and 42.9% at 12 months. Among the 18 eyes that underwent indocyanine green angiography both before and after treatment, 10 (55.6%) showed polyp regression. Overall, the incidence of intraocular inflammation (IOI), retinal vasculitis and occlusive retinal vasculitis was 9.4% (38 eyes), 1.2% (5 eyes)and 0.5% (2 eyes), respectively. IOI occurred from the first to the sixth injections, with an average IOI onset of 28.5 ± 1.4 days. All eyes achieved IOI resolution, although the two eyes with occlusive retinal vasculitis showed a severe visual decline after IOI resolution. Brolucizumab was effective in maintaining BCVA and managing fluid in eyes with nAMD for up to 1 year, exhibiting a high polyp regression rate. However, the not uncommon incidence of IOI and the severe visual decline caused by the rare occlusive retinal vasculitis following BRZ treatment underscore the importance of careful monitoring and timely management.

Effects of concurrent chemoradiotherapy with or without Endostar on the regression of retropharyngeal lymph node and prognosis of patients with locally advanced nasopharyngeal carcinoma: a retrospective study

Background and PurposeTo investigate the effect of combining Endostar with concurrent chemoradiotherapy (ECCRT) compared to concurrent chemoradiotherapy (CCRT) on the regression rate of retropharyngeal lymph nodes (RLNs) and the relationship between regression rate of RLNs and prognosis of patients with locally advanced nasopharyngeal carcinoma (LANPC).MethodsA total of 122 LANPC patients with RLNs metastasis were included. Metastatic RLNs were delineated both before and after treatment slice by slice on the magnetic resonance images cross-section. The regression rate of RLNs, adverse effects (AE) were evaluated. The median regression rate of RLNs was taken as the cut-off value, and the patients were furtherly divided into high regression rate (HRR) group and low regression rate (LRR) group, then survival times were evaluated.ResultsThe median regression rates of RLNs in the ECCRT and CCRT groups were 81% and 50%, respectively (P < 0.001). There was no statistically significant difference in the incidence of grade 3/4 AEs between the two groups, except for oral mucositis (ECCRT 26.23% vs. CCRT 44.26%, P = 0.037). The 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional failure-free survival (LRFFS) rates in the HRR and LRR groups were 85.48% and 86.67% (P = 0.983), 80.65% and 68.33% (P = 0.037), 83.87% and 85% (P = 0.704), 93.55% and 81.67% (P = 0.033), respectively.ConclusionsPatients in the ECCRT group had higher regression rates of RLNs and lower incidence of severe oral mucositis. Furthermore, patients in the HRR group had a better 3-year PFS and LRFFS rate than those in the LRR group.

Association Between Maternal Age and Postpartum Assessment of High-Grade Cervical Dysplasia Diagnosed in Pregnancy [ID 2683560

INTRODUCTION: The incidence of cervical dysplasia in pregnancy is expected to rise as patients delay childbearing. Historical studies have quoted high rates of postpartum regression of lesions diagnosed in pregnancy. We sought to evaluate the relationship between maternal age and postpartum progression, regression, and persistence of high-grade lesions. METHODS: This is a retrospective cohort study of patients with biopsy-proven high-grade dysplasia diagnosed during pregnancy from January 2013 to December 2022. Institutional review board approval was obtained. Only immunocompetent patients with postpartum pathology obtained within 1 year of delivery were included. Definitions based on postpartum pathology were as follows: regression as low-grade or resolved dysplasia, persistence as high-grade dysplasia, and progression as invasive cervical cancer. Results were stratified by maternal age (≤24, 25–29, 30–34, 35+) and data were analyzed using the Cochran–Armitage test. RESULTS: Among our cohort (N=286), 101 (35%) were diagnosed with CIN2, 181 (63%) with CIN3/CIS, and 4 (1%) with HSIL (not otherwise specified) on antepartum cervical biopsy. Average age was 28 (±4.2) years. Postpartum regression rate was 44% for patients aged 24 years or younger, 37% in ages 25–29, 33% in ages 30–34, and 33% in ages 35 or older (P=.174). Persistence was common (55%, 63%, 67%, and 64%, respectively) and apparent progression to cancer was rare, occurring in 1% of patients aged 24 years or younger and in 2.8% of patients 35 or older (P=.68). CONCLUSION: Persistence occurred in over half of patients, regardless of age. Our findings emphasize the importance of postpartum follow-up, and possible cervical excision, in patients with antepartum high-grade dysplasia.

Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147).

We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

Regression Rate and Combustion Efficiency of Composite Hybrid Rocket Grains Based on Modular Fuel Units

This study investigated combustion characteristics of composite fuel grains designed based on a modular fuel unit strategy. The modular fuel unit comprised a periodical helical structure with nine acrylonitrile–butadiene–styrene helical blades. A paraffin-based fuel was embedded between adjacent blades. Two modifications of the helical structure framework were researched. One mirrored the helical blades, and the other periodically extended the helical blades by perforation. A laboratory-scale hybrid rocket engine was used to investigate combustion characteristics of the fuel grains at an oxygen mass flux of 2.1–6.0 g/(s·cm2). Compared with the composite fuel grain with periodically extended helical blades, the modified composite fuel grains exhibited higher regression rates and a faster rise of regression rates as the oxygen mass flux increased. At an oxygen mass flux of 6.0 g/(s·cm2), the regression rate of the composite fuel grains with perforation and mirrored helical blades increased by 8.0% and 14.1%, respectively. The oxygen-to-fuel distribution of the composite fuel grain with mirrored helical blades was more concentrated, and its combustion efficiency was stable. Flame structure characteristics in the combustion chamber were visualized using a radiation imaging technique. A rapid increase in flame thickness of the composite fuel grains based on the modular unit was observed, which was consistent with their high regression rates. A simplified numerical simulation was carried out to elucidate the mechanism of the modified modular units on performance enhancement of the composite hybrid rocket grains.

Mitochondrial encephalopathies and myopathies: Our tertiary center's experience

Mitochondrial diseases have a heterogeneous phenotype and can result from mutations in the mitochondrial or nuclear genomes, constituting a diagnostically and therapeutically challenging group of disorders. We report our center's experience with mitochondrial encephalopathies and myopathies with a cohort of 50 genetically and phenotypically diverse patients followed in the Neurology clinic over the last ten years. Seventeen patients had mitochondrial DNA mutations, presented over a wide range of ages with seizures, feeding difficulties, extraocular movements abnormalities, and had high rates of stroke-like episodes and regression. Twenty-seven patients had nuclear DNA mutations, presented early in life with feeding difficulty, failure-to-thrive, and seizures, and had high proportions of developmental delay, wheelchair dependence, spine abnormalities and dystonia. In six patients, a mutation could not be identified, but they were included for having mitochondrial disease confirmed by histopathology, enzyme analysis and clinical features. These patients had similar characteristics to patients with nuclear DNA mutations, suggesting missed underlying mutations in the nuclear genome. Management was variable among patients, but outcomes were universally poor with severe disability in all cases. Therapeutic entryways through elucidation of disease pathways and remaining unknown genes are acutely needed.

The efficacy and safety of PD-1 inhibitor combined with TACE in the first-line treatment of unresectable hepatocellular carcinoma.

The application of immune checkpoint inhibitors (ICIs) has changed the treatment of advanced hepatocellular carcinoma. Transcatheter arterial chemoembolization (TACE) is a first-line treatment for intermediate hepatocellular carcinoma. Serving as a local treatment modality that can induce immunogenic cell death, the efficacy and safety of combined use with ICI have not been evaluated. Although there have been prospective studies aimed at evaluating the efficacy and safety of ICI combined with TACE in BCLC stage B HCC patients, there are few reports on the evaluation of BCLC stage C patients with distant metastasis or portal vein cancer thrombus. Data of unresectable hepatocellular carcinoma patients received PD-1 inhibitor and TACE were collected in Xijing Hospital from June 2019 to December 2022. The tumor response was evaluated according to the Solid Tumor Modified Response Evaluation Standard (mRECIST), including complete response (CR), partial response (PR), disease stability (SD), disease progression (PD), objective response rate (ORR), and disease control rate (DCR). The progression-free survival (PFS) and overall survival (OS) were used to estimate therapy efficacy. The treatment-related adverse events were evaluated based on National Cancer Institute Common Adverse Event Evaluation Criteria (CTCAE) version 5.0. A total of 42 patients with unresectable hepatocellular carcinoma were included in this study, including 34 males (80.5%) and 8 females (19.5%). The average age is 54.5years, ranging from 34 to 72. The median follow-up time was 12.3months, with an ORR of 42.9% and a DCR of 90.5% as of the follow-up time. The median PFS is 7.5months (95% CI: 5.76-9.23), and the median OS has not yet been reached; 6-month PFS was 62.2%. Safety analysis showed that 41 (97.6%) patients experienced treatment-related adverse reactions, mainly including elevated AST and ALT, fever, elevated bilirubin, hypothyroidism, nausea, abdominal pain, and rash. 40 patients had grade 1/2 adverse reactions, and only one patient had grade 3 adverse reactions, manifested as intolerable rash, nausea, and vomiting. Treatment is terminated when symptomatic treatment and drug suspension cannot be alleviated. In this study, thre patients with unresectable hepatocellular carcinoma were treated with PD-1 inhibitor combined with TACE to achieve good tumor reduction effect and underwent liver cancer resection surgery. For patients with unresectable hepatocellular carcinoma, whether in BCLC stage B or stage C, effective systemic therapy (PD-1 inhibitor) combined with local therapy (TACE) can achieve a high rate of tumor regression and objective response. Some patients may even pursue surgical treatment opportunities, and the treatment-related adverse reactions are controllable, which is expected to provide new options for extending the survival of unresectable hepatocellular carcinoma patients.

Abstract 4104: Randomized phase II trial of imiquimod with or without 9vHPV vs observation in patients with CIN 2 and 3

Abstract Introduction: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator, vs imiquimod plus a 9-valent human papillomavirus vaccine (9vHPV) vs surveillance in cervical intraepithelial neoplasia (CIN) 2 and 3 patients. Methods: We randomly allocated 133 patients with untreated CIN 2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (arm B) or imiquimod plus 9vHPV (arm C) vs clinical surveillance (arm A). The main outcome was efficacy, defined as histologic regression to CIN 1 or less. Secondary outcomes were HPV clearance and treatment tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and post-treatment by flow-cytometry. Results: Of the 114 evaluable patients 77% and 23% had CIN2 and CIN3, respectively. Histologic regression to CIN1 or less was observed in 95% of patients in the Arm B: imiquimod group and 84% in the Arm C: imiquimod+9vHPV compared with 79% in Arm A: surveillance (p=0.043 and 0.384, respectively). The difference between either treatment arm compared with control did not reach the prespecified α=0.025. No significant differences were noted in HPV clearance. The number of tissue-resident memory CD4/CD8 T-cells in cytobrush samples demonstrated a &amp;gt;5-fold increase in Arm-B: imiquimod when compared to Arm-A: surveillance (p&amp;lt;0.01). Imiquimod treatment was well tolerated. In contrast, there was no significant difference in T-cell responses among participants in Arm-C compared to Arm-A. Imiquimod treatment was well-tolerated. Conclusions: Although imiquimod induced a higher percentage of regression to CIN1 or less and significant increases in CD4/CD8 T-cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trial with imiquimod targeting CIN3 patients are warranted. Citation Format: Sangini S. Sheth, Ji Eun Oh, Stefania Bellone, Eric R. Siegel, Natalia Buza, Akiko Iwasaki, Alessandro D. Santin. Randomized phase II trial of imiquimod with or without 9vHPV vs observation in patients with CIN 2 and 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4104.

Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy

BackgroundImmunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency.MethodsHerein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes.ResultsThe SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1 ± 5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu.ConclusionsEventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments.Graphical

Is robotic-assisted vaginectomy a better choice in vaginal high-grade squamous intraepithelial lesions than conventional laparoscopic surgery?

BackgroundVaginectomy has been shown to be effective for select patients with vaginal high-grade squamous intraepithelial lesions (HSIL) and is favored by gynecologists, while there are few reports on the robotic-assisted laparoscopic vaginectomy (RALV). The aim of this study was to evaluate the safety and treatment outcomes between RALV and the conventional laparoscopic vaginectomy (CLV) for patients with vaginal HSIL.MethodsThis retrospective cohort study was conducted in 109 patients with vaginal HSIL who underwent either RALV (RALV group) or CLV (CLV group) from December 2013 to May 2022. The operative data, homogeneous HPV infection regression rate and vaginal HSIL regression rate were compared between the two groups. Student’s t-test, the Mann-Whitney U test, Pearson χ2 test or the Fisher exact test, Kaplan-Meier survival analysis and Cox proportional-hazards models were used for data analysis.ResultsThere were 32 patients in the RALV group and 77 patients in the CLV group. Compared with the CLV group, patients in the RALV group demonstrated less estimated blood loss (41.6 ± 40.3 mL vs. 68.1 ± 56.4 mL, P = 0.017), lower intraoperative complications rate (6.3% vs. 24.7%, P = 0.026), and shorter flatus passing time (2.0 (1.0–2.0) vs. 2.0 (2.0–2.0), P < 0.001), postoperative catheterization time (2.0 (2.0–3.0) vs. 4.0 (2.0–6.0), P = 0.001) and postoperative hospitalization time (4.0 (4.0–5.0) vs. 5.0 (4.0–6.0), P = 0.020). In addition, the treatment outcomes showed that both RALV group and CLV group had high homogeneous HPV infection regression rate (90.0% vs. 92.0%, P > 0.999) and vaginal HSIL regression rate (96.7% vs. 94.7%, P = 0.805) after vaginectomy. However, the RALV group had significantly higher hospital costs than that in the CLV group (53035.1 ± 9539.0 yuan vs. 32706.8 ± 6659.2 yuan, P < 0.001).ConclusionsBoth RALV and CLV can achieve satisfactory treatment outcomes, while RALV has the advantages of less intraoperative blood loss, fewer intraoperative complications rate and faster postoperative recovery. Robotic-assisted surgery has the potential to become a better choice for vaginectomy in patients with vaginal HSIL without regard to the burden of hospital costs.

Studying the paraffin based mixtures regression under high speed hot air blowing

Hybrid and ramjet engines became now effective propulsion systems with great development potential in different fields. They require using proper high-energy components. At high-speed blowing conditions conventional polymer fuels exhibit relatively low regression rate. As an alternative, it is proposed to use paraffin and based on it compositions. Paraffin is high-energy hydrocarbon with a low melting point leading to a high regression rate in high-speed blowing conditions. The results of experimental study of regression behavior of paraffin mixtures with various additives under intensive hot air blowing at 1 MPa pressure are presented. Stearic acid, nanoaluminum Alex, aluminum hydride AlH3, B and mechanoactivated aluminum boride AlB2 were used as 10 % by mass additives. Experiments were conducted on cylindrical perforated samples. Using original design microwave gauge the current diameter of a sample bore was measured during experiment with subsequent calculation of regression rate. Based on experimental data and the results of heat balance calculation, the temperature on the gasified surface of paraffin fuel was estimated.

Midterm outcomes of physician-modified endovascular stent grafts for the treatment of complex abdominal aortic aneurysms in Korea: a retrospective study.

Physician-modified endovascular stent grafts (PMEG) are a good treatment option for complex abdominal aortic aneurysms (AAAs), especially in high-risk patients not amenable to open repair, and when commercial fenestrated devices are not available. We report our single-center experience with PMEG for the treatment of complex AAAs. We retrospectively reviewed patients who underwent PMEG repair for AAA from November 2016 to September 2020 at our institution. Demographic data, anatomic characteristics, perioperative and postoperative outcomes, major adverse events, and 30-day mortality were analyzed. We identified 12 patients who underwent PMEG for complex AAA. The mean age was 74 years and the mean maximal AAA diameter was 58.1 mm. Indications for treatment included 4 impending or contained ruptures, 2 mycotic aneurysms, and 6 symptomatic cases. The technical success rate was 91.7%. Aneurysm sac regression was observed in 7 patients (58.3%), including 2 cases of complete regression. There was 1 aneurysm-related mortality at 3 months due to mycotic aneurysm. Also, there was 1 postoperative complication case of transient renal failure requiring temporary dialysis. At 1 year, there was 1 branch occlusion from the initial failed cannulation case and 2 type 1A endoleaks, and there was 1 case of open explantation. PMEG showed a low technical failure rate and acceptable midterm stent durability and sac stability, comparable to conventional endovascular aneurysm repair. Despite the small number of cases, there was a tendency for a high sac regression rate, although longer follow-up is needed.